Not a single plaque-preventing drug has yet gained FDA approval. There are currently hundreds of drugs in development to combat the symptoms – and hopefully the causes – of AD. Many of these drugs are aimed at blocking the formation of beta amyloids, peptides that cause plaque deposits in the brains of AD patients. But are the plaques the cause of neuron loss? The amyloid hypothesis is still unproven, and not all research supports it. The FDA is holding the bar high: until a drug can not only show that it blocks plaque formation safely, but preserves cognitive capacity in AD subjects, none of these drugs will make it to market.

Testing whether or not a drug prevents cognitive degeneration can take years or decades – basically as long as takes for the disease to reach advanced stages. This presents pharmaceutical companies with a regulatory conundrum. Let’s say a company decides to test its drug on susceptible subjects before AD onset, catching the disease early and improving the likelihood of success. Clinical trials will take much longer – long enough for differences between subject groups to emerge.

The alternative approach is the one being taken by Bristol-Myers Squib, which is currently testing its new drug BMS-708163. BMS is testing the drug on early-stage patients, which means their trials will show results much faster than if they had tested subjects without any symptoms. But by waiting until the disease has already progressed into its early stages, they run the risk that their subjects’ degeneration has advanced beyond the period when the drug could have helped. Add in competition with other companies racing for the prize, and you get an idea of the stakes involved.

AD causes severe brain degeneration compared with that of a healthy person.

The link between amyloids and AD was first proposed when the gene that codes for amyloid precursor protein was found on chromosome 21. People with Down syndrome have an extra copy of chromosome 21 (i.e. an extra copy of the amyloid precursor gene), and they commonly develop AD early in life. People with the E4 variant of the gene ApoE also produce more amyloid plaques, and it increases their susceptibility to AD. (We recently covered a study of how people react to hearing that they carry this risk variant).

So why is the FDA holding these drugs to such high standards? It isn’t clear that amyloid plaques are actually the cause of neuron death. A few years ago, an amyloid vaccine was tested on patients with AD; seven of the eight immunized patients died with severe dementia, even after partial or complete plaque removal. Scientists have been tweaking the amyloid theory since, and new treatments do hold promise. But the FDA is wary of approving a drug that clears plaque without stopping or slowing the disease itself.

AD currently affects over 26 million people, and those numbers are rising as the world population ages. A few years ago, a study at Johns Hopkins described a “looming global epidemic” of Alzheimer’s: the number of cases will quadruple within forty years, ultimately affecting 1 in 85 people globally. Whatever its cause, the slow progression of AD makes clearing drug treatments a terribly slow process – and one all the more important for the wave to come.

[images: Emiliano Ponzi, Northwestern University; CSIRO]

It's Alive!

Who says biology, engineering, and medicine are different fields? Researchers led by Dr. Donald Ingber at Harvard’s Wyss Institute reported in Science that they have engineered a coin-sized microchip that can be loaded with wet biological cells, mimicking the workings of an actual lung. The bioinspired chip can be used to model drug action, determine the effects of environmental toxins, and could even replace some animal testing – all while speeding up research and dropping its costs.

To mimic the physiology of an actual lung, the chip contains two chambers separated by a flexible, porous membrane. One chamber contains human lung cells (alveoli), which are tiny air sacs with thin walls – this chamber allows researchers to introduce foreign particles, just as breathing would do in an organism. Across the membrane, the second chamber contains capillary blood cells (endothelium) which normally take up particles into the blood stream, as well as interface the immune system with potential toxins and pathogens. The computer chip is transparent, which allows real-time observation of how the cells respond to introduced particles.

Did I mention it also breathes? Because the chip is flexible, fluctuating the air pressure within a network of channels along its surface can replicate the mechanics of breathing – stretching and expanding the cells inside the chambers, roughly as they would in real life. This capacity for the chip to mimic breathing is an important step forward, because cell culture techniques are unable to replicate how mechanical factors influence cell behavior. Filling this gap brings laboratory models closer to the real-world organs they try to represent. Think of it as a miniature version of the donated lungs made to breathe outside the body.  Check out this video of lead researcher Donald Ingber talking about the chip:

Researchers’ first test of the lung-chip looked at how the system responded to the introduction of a pathogen. E. coli was added to the first chamber containing lung cells, mimicking the exposure of lungs to airborne bacteria. The second chamber was given a healthy dose of white blood cells (leukocytes), which are the immune system’s first line of defense against foreign invaders. Show time. Through the transparent chip, researchers watched in real time as the white blood cells migrated across the porous membrane, engulfing and killing the bacterial invaders. The chip clearly modeled the body’s own inflammatory response to pathogens.

The lung-chip design, and the biological processes it models.

A second test looked at how the lung-chip responded to the introduction of nanoparticles comparable to those found in toxic pollutants. Some of the particles induced an immune response and were trapped; others crossed the chip’s membrane and entered the blood chamber. Using the chip to model the introduction of non-biological particles illustrates how some toxins can make their way past the immune system and invade the body. It also provides an excellent system to test how airborne drugs are taken up into the lungs, which will cut costs and save time in the development of inhaled medications.

The next step? Currently, the cells used come from immortalized cell lines, which aren’t patient-specific and only provide a kind of average response to different drugs. If the lung-chip could be loaded with “primary” cells from an individual patient, testing could determine individual responses to potential drug action. Induced pluripotent stem cells, which can be derived from a patient’s skin, could be stimulated into alveoli and endothelium cells and provide a personalized lung-chip for specific testing. This would fit well into the larger movement towards patient-specific medicine.

The lung-chip isn’t quite ready for broad application yet – it still needs to be cross-compared with current methods of testing inhalant effects, which use rats as experimental organisms. If these comparisons show that the chip accurately mimics a normal lung, it could eventually mean an end to animal testing for this type of research. In addition to the obvious win for animal rights folks, the chip would save time and money by replacing costly animal research.

Future research will plan to apply comparable techniques to other organs of the body – a gut-chip, kidney-chip, heart-chip, etc. This will help us understand how drugs and toxins effect the body more broadly. Imagine having a series of personalized chips for all your different organs – your doctors could custom-test any potential treatment against miniature models of your own body. The computer/body interface is already being explored with chips that can detect cancer or identify bacterial strains within the body; the lung-chip represents an exciting new application of this hybrid technology outside the body.

It’s worth recognizing how exciting the Wyss Institute itself is.  Founded last year by Ingber himself, the institute is devoted to biologically-inspired engineering: figuring out mother nature’s tricks, and replicating them in man-made systems. The faculty list reads like a who’s-who of biology (George Church and James Collins, to name a few) and if this research is any indication, we can expect more exciting research from this group in the future.

As it stands, the lung-chip is an amazing example of how biology is creating new frontiers in engineering: an impressive reminder of the sort of human-machine interface that represents the future of medicine, and potentially ourselves.

See below an exclusive pic sent to us directly from Dr. Ingber:

The blue is the lung side, the red is the vasculature side

[images courtesy of Image: Kristin Johnson/Harvard Medical School/Science]

They should have checked their calenders. WABDA (a pun on the real-life WADA) was an April Fools brainchild of UC Davis biologist Jonathan Eisen, who coordinated the prank with a number of friends and even set up a website for the organization. While the news was fake, it struck a very real nerve. The viral spread of the prank revealed an actual anxiety should the NIH start collecting urine samples. Ten days later, an informal survey in Nature showed why.

Of 1,427 people working at scientific institutions in over 60 countries, about 20% of the respondents admitted to using brain-enhancing drugs for non-medical purposes. The most popular drug was Ritalin, a drug that treats ADHD, with 62% of users. The second most popular was Provigil, a drug to improve awakeness in narcoleptics; 44% of users take it. 15% of users admitted to using beta-blockers, drugs designed for cardiac arrhythmias which have an anti-anxiety effect. Most respondants reported that they used the drugs to improve their concentration, memory and focus. Others pointed to treating jet-lag, partying, housecleaning, and a wide variety of other purposes.

Surprise, surprise. Drugs and science have a long history together. Kary Mullis won the Nobel Prize for his invention of Polymerase Chain Reaction (PCR), the laboratory foundation of modern genetics. He later divulged to Albert Hofmann, the late Swiss chemist who first synthesized LSD, that the drug helped him to develop the technique. Similar rumors surround Francis Crick’s realization about the double-helix structure of DNA (another “eureka” of Nobel Prize fame).

Should we be outraged? After all, Barry Bonds made headlines worldwide when it was revealed that he took performance-enhancing drugs. The Tour de France is plagued by accusations of drug use, and fans are justifiably angry when tests return positive. How is mental exercise any different? Why should some scientists have a chemical edge over others?

For one thing, as much as it might resemble one, science is not a competition sport. The logic behind anti-doping regulations in sports makes perfect sense; one athlete with a chemical advantage ruins the idea of fair competition, which is the foundation of sports in general. Watching Michael Jordan dunk is less impressive if we know he was just injected with testosterone. Science, on the other hand, is fundamentally a quest for knowledge of the world we live in.  If a scientist can unveil new revelations about our world, is that knowledge less true because chemicals influenced the discovery?

Even in competive testing – the SAT or GRE, for example – the lines get blurry. I can personally attest to gulping a big, fat cup of coffee before every major examination of my life; is this so different from pharmaceutical enhancements? Where can we draw the line? The essential difficulty here is that any “baseline level of performance” – from which drug use is a supposed departure – is an imaginary concept. Our bodies are built differently, and have different baseline performances (mental and otherwise). Drugs like Adderall help those with ADHD to function at a higher level than their personal baseline (diagnosed as a subnormal capacity for attention).  Does Adderall bring them back up to average? Slightly above or below average?  What is an average attention span, anyway?

This is not to suggest that these drugs don’t help millions to function in the world – they do. But the field of psychology is notoriously plagued by the difficulties of diagnosis, simply because pathologies aren’t as clear as black and white. They occur in many shades of grey, and defining “normal” (and basing diagnoses on it) is both a difficult and a political act.

The first step to a responsible consideration of brain boosters is to consider the vague definition of drugs themselves. Caffeine, the most widely used drug on the planet, is socially accepted as a “fair” mental performance enhancer. Prescription drugs, to many, still fall within the paradigm of medical science as cures to pathologies.  But – as the numbers show – a growing number of scientists feel differently, and use the drugs to boost their healthy brains. They’re not the only ones.

If trends today are any indication, our species’ course is one that increasingly blends our biological bodies with our technologies. Prosthetics are happily invited to restore functionality to lost limbs. Vaccines and antibiotics allow us to hack our immune system to keep us healthier. Hell, we wear clothes! Today, brain boosters are eyed suspiciously outside of their medical context. Maybe (just maybe) our grandkids will think differently. Not to mention faster, more clearly, and with a great attention span.